Relapse to drug abuse following abstinence is a significant impediment in the treatment of cocaine dependence. Although various factors (stress, conditioned cues, drugs) that contribute to relapse have been studied in males, the impact in females has been less explored. We have recently shown sex differences for conditioned cue-induced and drug-primed reinstatement of cocaine-seeking in an animal model of relapse. Moreover, the differences seen in females are closely linked to the estrus phase of the estrous cycle. Building on these previous studies, this SCOR project will provide a comprehensive approach to examine sex and estrous cycle dependent differences in reinstatement of cocaine-seeking produced by various trigger factors. Using direct pharmacological activation of the neural pathways that mediate stress responses (e.g., ascending noradrenergic pathways and corticotropin-releasing factor receptors) we predict that female rats (particularly during the estrus phase) will show greater reinstatement of cocaine-seeking than male rats exposed to the same stressor. The use of the exact same stressors and cue reactivity approaches in both the animal model and the human clinical laboratory (SCOR Project #2),will provide a high degree of homology and integration. Following characterization of stress and stress+cue induced reinstatement in males and females, we will examine sex and estrous cycle dependent pharmacotherapy interventions that will attenuate relapse, specifically: a) clonidine, a noradrenergic receptor agonist that may selectively block stress-induced reinstatement;b) progesterone, an ovarian hormone that we have recently found to be inversely related to cocaine-seeking in females;and c) aripiprazole, a novel dopamine receptor partial agonist that blocks cue and drug-primed reinstatement in males, but has never been tested in females. The information gained from these studies will integrate with the clinical SCOR projects that will focus on gender differences and relapse in cocaine (Project #2) and nicotine (Project #4) dependent women andmen, including the relationship of ovarian hormones to drug-seeking. In addition, this project will parallel the preclinical animal model of sex and estrous cycle dependent differences in nicotine-seeking and reinstatement in Project #3. This preclinical animal model of relapse will characterize fundamental sex and estrous cycle dependent differences in cocaine-seeking behavior produced by known risk factors for relapse in humans (i.e., stress, cues, drugs). Furthermore, we will assess pharmacotherapies that may be generalized across males and females, as well as interventions that may be gender-specific. The results from these studies will help identify promising pharmacotherapeutic agents for future testing in the human laboratory setting.